Pharmacokinetic and pharmacodynamic integration and resistance analysis of cefquinome against Streptococcus uberis in vitro dynamic model

Abstract

Introduction: Streptococcus uberis (S. uberis) is a major pathogen that causes acute clinical mastitis and its recurrent episodes in dairy cows.

Methods: In this study, a peristaltic pump one-compartment open model was established to investigate the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) indices of cefquinome (CFQ) against S. uberis. Bactericidal effects of single high-dosage versus multiple low-dosage administrations within the same drug dosage and best-fit dosage were assessed.

Results: Static time-killing curves showed that the population of S. uberis was not changed when the drug concentration was below 1 × MIC. The maximum antibacterial effect was observed at 24 h, when the concentration exceeded 2 × MIC, showing a reduction by 5.73 log₁₀ (CFU/mL), and the maximum kill rate was 0.22 h^-1. S. uberis were cleared at 120 h when the concentration was ≥1 mg/L within single high-dosage groups, except for the 0.28 and 0.5 mg/L groups. The multiple-dose groups decreased below 2.22 log₁₀ (CFU/mL) at 48 h and increased to 9 log₁₀ (CFU/mL) at 120 h, but the group of 0.25 mg/L (4, q24) increased at 144 h. As the frequency of administration increased, the lag time increased following a population decline. The correlation coefficients between AUC_0-72h/MBC, %T > MBC, and the antibacterial effects were 0.90 and 0.99%, respectively. %T > MBC was the best-fit PK/PD parameter of CFQ against S. uberis. The MIC of S1-S5 strains ranged from 0.0156-0.0625 μg/mL, and biofilm formation ability increased.

Discussion: In conclusion, CFQ showed good efficacy and time-dependence. This study provides a reference for optimizing CFQ administration in S. uberis.

Keywords: dynamic model; multiple low-dosage; pharmacodynamic; pharmacokinetic; simulation; single high dosage.

Figure 1

The in vitro dynamic model simulates the pharmacokinetics of cefquinome and the bactericidal effect and susceptibility of S. uberis. EC, external compartment; IC, internal compartment.

Figure 2

Time-killing studies of cefquinome against S. uberis at different concentrations. Data are presented as geometric means of three experiments. MIC, minimum inhibitory concentration; CFU, colony forming units.

Figure 3

The best-fit curve obtained from the E_max model of static time-killing assay data. R² is the correlation coefficient.

Figure 4

Dynamic time-killing curves depicted at two dosage regimens. Data points represent geometric means of three experiments.

Figure 5

Concentration-time curves of cefquinome in the in vitro dynamic model. The dosage regimen of 0.09 mg/L (3, q24) is not presented because the concentration is below the limit of quantification.

Figure 6

The curve of the PK/PD parameters versus the antibacterial effect. (A) %T > MBC-antibacterial effect curve; (B) AUC_0-72h/MBC-antibacterial effect curve. R² is the correlation coefficient. AUC, area under the concentration-time curve; %T > MBC is the time percentage that the concentration exceeds the MBC.

Figure 7

The biofilm formation ability of S1–S5.

Figure 8

The flowchart of the main procedures in the study.

Figure 9

The main results of the study.